Enantioselective hydrogenation of 4-substituted 1, 2-dihydroquinolines in presence of chiral iridium (P, S)-ligand catalysts

Abstract

The present invention relates to a process for the preparation of optically active 4-substituted 1, 2, 3, 4-tetrahydroquinoline, said process comprising the enantioselective hydrogenation of the corresponding 4-substituted 1, 2-dihydroquinoline in the presence of a chiral iridium (P, S)-ligand catalyst.

Description

[0001] This invention relates to a method for preparing optically active 4-substituted 1,2,3,4-tetrahydroquinoline, the method comprising enantioselectively hydrogenating the corresponding 4-substituted 1,2-dihydroquinoline in the presence of a chiral iridium complex having a specific chiral chelating ligand comprising at least one phosphorus atom and at least one sulfur atom, both bonded to an iridium atom, hereinafter also referred to as a "chiral (P,S)-ligand".

[0002] 4-Substituted 1,2,3,4-Tetrahydroquinolines are multifunctional intermediates for the synthesis of N-indanyl heteroaryl carboxylamide fungicides, including the recently introduced pyrazole carboxylamide fungicide inpyrfluxam (EP0654464, WO2015 / 141564, WO2019 / 185541, WO2021 / 058457, WO2021 / 058458). They can be obtained by hydrogenating the corresponding 4-substituted 1,2-dihydroquinolines.

[0003] WO 2015 / 141564 discloses a method for preparing optically active 4-substituted 1,2,3,4-tetrahydroquinolines, comprising hydrogenating the corresponding 4-substituted 1,2-dihydroquinolines in the presence of a transition metal catalyst having optically active ligands. The reported asymmetric hydrogenation of 4-substituted NH-dihydroquinolines was carried out with moderate conversions (up to 62.6%) and enantioselectivity (up to 71.3% ee), while the hydrogenation of N-acetyldihydroquinolines exhibited even lower conversions (up to 14%) and enantioselectivity (up to 31% ee).

[0004] WO 2019 / 185541, WO 2021 / 058457, and WO 2021 / 058458 disclose the enantioselective hydrogenation of 4-substituted 1,2-dihydroquinolines in the presence of specific chiral iridium (P,N)-ligand catalysts, which provide improved conversion and enantioselectivity. These chiral iridium (P,N)-ligand catalysts exhibit excellent catalytic activity. However, the synthesis of the corresponding chiral iridium (P,N)-ligand catalysts is complex, and the regeneration and recycling of depleted catalysts are difficult.

[0005] Therefore, there is a need for a method for the enantioselective hydrogenation of 4-substituted 1,2-dihydroquinolines that offers advantages over known methods in the prior art. The object of this invention is to provide such a method, particularly one capable of obtaining the desired product with high conversion and enantioselectivity, and employing catalysts obtained via less complex synthetic routes and / or catalysts that are easily regenerated and recycled.

[0006] The above objective is achieved by the method of the present invention, namely, a method for preparing compounds of formula (Ia) or (Ib): R 1 Selected from C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl, C6-C 14 -Aryl, and C6-C 14 -aryl-C1-C4-alkyl, In the C1-C6-alkyl, C3-C6-cycloalkyl, and C1-C6-alkoxy-C1-C6-alkyl moieties, the C1-C6-alkoxy group is unsubstituted or substituted with one to three substituents independently selected from halogens, C1-C4-alkoxy groups, C1-C4-haloalkyl groups, C1-C4-haloalkoxy groups, and phenyl groups, wherein the phenyl group is unsubstituted or substituted with one to five substituents independently selected from halogens, C1-C4-alkyl groups, C1-C4-alkoxy groups, C1-C4-haloalkyl groups, and C1-C4-haloalkoxy groups, and... Among them, C6-C 14 -Aryl and C6-C 14 C6-C of the aryl-C1-C4-alkyl moiety 14 -The aryl group is, in its respective case, unsubstituted, or substituted by one to five substituents independently selected from halogens, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, and C1-C4-haloalkoxy groups. R 2 With R 3 The same, and selected from hydrogen, C1-C6-alkyl, C1-C6-haloalkyl, and C1-C6-alkoxy-C1-C6-alkyl. or R 2 With R 3 Together with the carbon atom it is attached to, it forms a C3-C6 cycloalkyl ring. R 4 Selected from hydrogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylamino, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-C1-C4-alkyl, C2-C6-alkenyloxy, 9-fluorenylmethyleneoxy, C6-C 14 -Aryl, C6-C 14 -Aryloxy group, C6-C 14 -aryl-C1-C4-alkyloxy and C6-C 14 -aryl-C1-C4-alkyl, Among them, C6-C is a component of independent substituents or complex substituents. 14 -The aryl group is unsubstituted or substituted by one to five substituents independently selected from halogens, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, and C1-C4-haloalkoxy groups. n is 0, 1, 2, 3, or 4. Each substituent R 5 (If present) independently selected from halogens, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, hydroxyl, amino, and -C(=O)-C1-C6-alkyl. The method comprises enantioselectively hydrogenating compounds of formula (II) in the presence of a chiral iridium catalyst. Among them, substituent R 1 R 2 R 3 R 4 R 5 And an integer n, each defined as a compound of formula (Ia) or (Ib), characterized in that the chiral iridium catalyst contains a chiral ligand of formula (IIIa) or (IIIb). in R 6 For C6-C 14 -aryl group, which is either unsubstituted or substituted with 1 to 5 substituents independently selected from C1-C4-alkyl groups. R 7 Selected from phenyl, naphthyl, and anthracene, The phenyl group is substituted with 1 to 5 substituents independently selected from C1-C4-alkyl groups, and the naphthyl and anthracene groups are either unsubstituted or substituted with 1 to 5 substituents independently selected from C1-C4-alkyl groups. Each R 8 For C6-C 14 -aryl group, which is substituted by 1 to 5 substituents independently selected from C1-C4-alkyl groups. R 9 Selected from C1-C6-alkyl, C3-C8-cycloalkyl and C6-C 14 -Aryl Wherein, the C1-C6-alkyl and C3-C8-cycloalkyl groups are unsubstituted or substituted with 1 to 3 substituents independently selected from halogens, C1-C4-alkoxy groups, C1-C4-haloalkyl groups, C1-C4-haloalkoxy groups, and phenyl groups, wherein the phenyl group is unsubstituted or substituted with 1 to 5 substituents independently selected from halogens, C1-C4-alkyl groups, C1-C4-alkoxy groups, C1-C4-haloalkyl groups, and C1-C4-haloalkoxy groups, and, Among them, the C6-C 14 -The aryl group is unsubstituted or substituted by one to five substituents independently selected from halogens, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, and C1-C4-haloalkoxy groups. or R 9 The carrier material is selected from polyether, polystyrene, silica and alumina.

[0007] Surprisingly, the optically active 4-substituted 1,2,3,4-tetrahydroquinolines of formulas (Ia) and (Ib) can be prepared in high yields and with enantioselectivity by enantioselective hydrogenation of the corresponding 4-substituted 1,2-dihydroquinoline of formula (II) in the presence of the aforementioned specific chiral iridium (P,S)-ligand catalysts. Compared to the catalysts known in WO 2019 / 185541, WO 2021 / 058457, and WO 2021 / 058458, the synthesis of these catalysts requires fewer steps, and they can be immobilized on a solid support via ether functional groups to form heterogeneous catalyst systems that are easily separated from and recycled from the product mixture.

[0008] The chiral iridium (P,S)-ligand catalysts used in the methods of this invention and their synthesis methods have been disclosed in detail by J. Margalef et al. in Chem. Eur. J. 2014, 20, 12201-12214, or similarly thereof. Although the chiral iridium (P,S)-ligand catalysts known from the aforementioned references contain (P,S)-ligands of formula (IIIa) or (IIIb) (wherein R...) 7 It is tert-butyl or unsubstituted phenyl and / or R 8 (for unsubstituted phenyl), but in the enantioselective hydrogenation of 4-substituted 1,2-dihydroquinoline of formula (II), satisfactory conversion and enantioselectivity were not achieved. Surprisingly, this was achieved by using (P,S)-ligands containing formula (IIIa) or (IIIb) (where R is unsubstituted phenyl), but in the enantioselective hydrogenation of 4-substituted 1,2-dihydroquinoline of formula (II), satisfactory conversion and enantioselectivity were not achieved. 7 For substituted phenyl, naphthyl, or anthracene, and R 8 To replace C6-C 14 -Aryl, i.e., R7 and R 8 When hydrogenation is carried out in the presence of a chiral iridium catalyst (both residues have high steric hindrance), good conversion and enantioselectivity can be obtained. No information in the literature of J. Margalef et al. points to this specific substitution mode.

[0009] definition In the symbol definitions given in the above chemical formulas, collective terms are used, which generally represent the following substituents: halogen: fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, and more preferably fluorine or chlorine.

[0010] Alkyl: A saturated straight-chain or branched hydrocarbon substituent having 1 to 6, preferably 1 to 4, carbon atoms, such as (but not limited to) C1-C6-alkyl, for example, methyl, ethyl, propyl (n-propyl), 1-methylethyl (isopropyl), butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1 -Dimethylpropyl, 1,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, and 1-ethyl-2-methylpropyl. In particular, the group is a C1-C4 alkyl group, such as methyl, ethyl, propyl, 1-methylethyl (isopropyl), butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), or 1,1-dimethylethyl (tert-butyl). Unless otherwise defined, this definition also applies to substituents used in complex structures (e.g., C3-C6-cycloalkyl-C1-C4-alkyl, C6-C...). 14 Alkyl groups (including aryl-C1-C4-alkyl groups, etc.) are alkyl groups.

[0011] Alkenyl: An unsaturated straight-chain or branched hydrocarbon substituent having 2 to 6, preferably 2 to 4, carbon atoms and a double bond at any location, such as (but not limited to) C2-C6-alkenyl, for example vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, isopropenyl, homoallyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl (Z)-But-1-enyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl (Z)-Pent-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3 -Methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl, (E)-3,3-dimethylprop-1-enyl, (Z)-3,3-Dimethylprop-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, 4-methylpent-4-enyl, 3-methylpent-4-enyl, 2-methylpent-4-enyl, 1-methylpent-4-enyl, 4-methylpent-3-enyl, (E)-3-methylpent-3-enyl, (Z)-3-methylpent-3-enyl, (E)-2-methylpent-3-enyl, (Z)-2-methylpent-3-enyl, (E)-1 -Methylpent-3-enyl, (Z)-1-methylpent-3-enyl, (E)-4-methylpent-2-enyl, (Z)-4-methylpent-2-enyl, (E)-3-methylpent-2-enyl, (Z)-3-methylpent-2-enyl, (E)-2-methylpent-2-enyl, (Z)-2-methylpent-2-enyl, (E)-1-methylpent-2-enyl, (Z)-1-methylpent-2-enyl, (E)-4-methylpent-1-enyl, (Z)-4-methylpent-1-enyl, (E)-3-methylpent-1-enyl, (Z)-3-methylpent-1-enyl, (E)-2-methylpent-1-enyl, (Z)-2-methyl Pentyl-1-enyl, (E)-1-methylpentyl-1-enyl, (Z)-1-methylpentyl-1-enyl, 3-ethylbut-3-enyl, 2-ethylbut-3-enyl, 1-ethylbut-3-enyl, (E)-3-ethylbut-2-enyl, (Z)-3-ethylbut-2-enyl, (E)-2-ethylbut-2-enyl, (Z)-2-ethylbut-2-enyl, (E)-1-ethylbut-2-enyl, (Z)-1-ethylbut-2-enyl, (E)-3-ethylbut-1-enyl, (Z)-3-ethylbut-1-enyl, 2-ethylbut-1-enyl, (E)-1-ethylbut-1-enyl, (Z)-1-ethylbut-1-enyl -alkenyl, 2-propylprop-2-enyl, 1-propylprop-2-enyl, 2-isopropylprop-2-enyl, 1-isopropylprop-2-enyl, (E)-2-propylprop-1-enyl, (Z)-2-propylprop-1-enyl, (E)-1-propylprop-1-enyl, (Z)-1-propylprop-1-enyl, (E)-2-isopropylprop-1-enyl, (Z)-2-isopropylprop-1-enyl, (E)-1-isopropylprop-1-enyl, (Z)-1-isopropylprop-1-enyl, 1-(1,1-dimethylethyl)vinyl, but-1,3-dienyl, pent-1,4-dienyl, hex-1,5-dienyl, or methylhexadienyl. In particular, the group is vinyl or allyl. Unless otherwise defined, this definition also applies to alkenyl groups that are part of a complex substituent.

[0012] Alkynyl: A straight-chain or branched hydrocarbon substituent having 2 to 8, preferably 2 to 6, more preferably 2 to 4 carbon atoms and a triple bond at any location, such as (but not limited to) C2-C6-alkynyl, for example, ethynyl, prop-1-alkynyl, prop-2-alkynyl, but-1-alkynyl, but-2-alkynyl, but-3-alkynyl, 1-methylprop-2-alkynyl, pent-1-alkynyl, pent-2-alkynyl, pent-3-alkynyl, pent-4-alkynyl, 2-methylbut-3-alkynyl, 1-methylbut-3-alkynyl, 1-methylbut-2-alkynyl, 3-methylbut-1-alkynyl, 1-ethylprop-2-alkynyl, hex-1-alkynyl, hex-2-alkynyl, hex-3-alkynyl, hex-4 -Alynyl, hex-5-ynyl, 3-methylpentan-4-ynyl, 2-methylpentan-4-ynyl, 1-methylpentan-4-ynyl, 2-methylpentan-3-ynyl, 1-methylpentan-3-ynyl, 4-methylpentan-2-ynyl, 1-methylpentan-2-ynyl, 4-methylpentan-1-ynyl, 3-methylpentan-1-ynyl, 2-ethylbutan-3-ynyl, 1-ethylbutan-3-ynyl, 1-ethylbutan-2-ynyl, 1-propylpropan-2-ynyl, 1-isopropylpropan-2-ynyl, 2,2-dimethylbutan-3-ynyl, 1,1-dimethylbutan-3-ynyl, 1,1-dimethylbutan-2-ynyl, or 3,3-dimethylbutan-1-ynyl. In particular, the ynyl group is ethynyl, propan-1-ynyl, or propan-2-ynyl. Unless otherwise defined, this definition also applies to alkynyl groups that are part of a complex substituent.

[0013] Alkylamino: Monoalkylamino or dialkylamino, wherein a monoalkylamino group represents an amino group having an alkyl residue containing 1 to 6 carbon atoms attached to a nitrogen atom. Non-limiting examples include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, and tert-butylamino; wherein a dialkylamino group represents an amino group having two independently selected alkyl residues containing 1 to 6 carbon atoms attached to a nitrogen atom. Non-limiting examples include N,N-dimethylamino, N,N-diethylamino, N,N-diisopropylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-isopropyl-N-n-propylamino, and N-tert-butyl-N-methylamino.

[0014] Alkoxy group: a saturated straight-chain or branched alkoxy substituent having 1 to 6, more preferably 1 to 4, carbon atoms, such as (but not limited to) C1-C6-alkoxy groups, such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy Oxyloxy, hexyloxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy, and 1-ethyl-2-methylpropoxy. Unless otherwise defined, this definition also applies to alkoxy groups that are part of a complex substituent.

[0015] Cycloalkyl: A monocyclic or polycyclic saturated hydrocarbon substituent having 3 to 12, preferably 3 to 8, more preferably 3 to 6 carbocyclic members, such as (but not limited to) cyclopropyl, cyclopentyl, cyclohexyl, and adamantyl. Unless otherwise defined, this definition also applies to cycloalkyl groups that are part of a complex substituent, such as C3-C6-cycloalkyl-C1-C4-alkyl.

[0016] Haloalkyl: Straight-chain or branched alkyl substituents having 1 to 6, preferably 1 to 4, carbon atoms (as described above), wherein some or all of the hydrogen atoms in these groups are replaced by halogen atoms as described above, such as (but not limited to) C1-C3-haloalkyl, for example, chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, and 1,1,1-trifluoropropyl-2-yl. Unless otherwise defined, this definition also applies to haloalkyl groups as part of a complex substituent.

[0017] The definitions of alkenyl and alkyne are similar to those of alkyl halogens, except that alkenyl and alkyne, rather than alkyl, are present as part of a substituent.

[0018] Halogenated alkoxy groups: straight-chain or branched alkoxy substituents having 1 to 6, preferably 1 to 4, carbon atoms (as described above), wherein some or all of the hydrogen atoms in these groups are replaced by halogen atoms as described above, such as (but not limited to) C1-C3-halogenated alkoxy groups, such as chloromethoxy, bromomethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 1-chloroethoxy, 1-bromoethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, and 1,1,1-trifluoroprop-2-oxy. Unless otherwise defined, this definition also applies to haloalkoxy groups that are part of a complex substituent.

[0019] Aryl group: A monocyclic, bicyclic, or tricyclic aromatic or partially aromatic substituent having 6 to 14 carbon atoms, such as (but not limited to) phenyl, naphthyl, tetrahydronaphthyl, anthraceneyl, indenyl, and indenylyl. It can be bonded to a higher-order general structure via any possible ring member of the aryl residue. The aryl group is preferably selected from phenyl, 1-naphthyl, 2-naphthyl, 9-phenanthyl, and 9-anthrayl. Phenyl is particularly preferred unless otherwise specified.

[0020] As used herein, the term "enantioselectivity" means that one of the two possible enantiomers that preferably form the hydrogenated product is either the enantiomer of formula (Ia) or the enantiomer of formula (Ib). "Enantiomer excess" or "ee" indicates the degree of enantioselectivity. The main enantiomer can be controlled by selecting a chiral ligand, for example by selecting a chiral ligand of formula (IIIa) or its corresponding enantiomer (ligand of formula (IIIb)).

[0021] The method of the present invention is used to prepare compounds of formula (Ia) or (Ib), preferably compounds of formula (Ia).

[0022] Compounds of preferred formula (Ia) or (Ib), especially (Ia), wherein the substituents are defined as follows: R 1 It is a C1-C6-alkyl or C6-C 14 -aryl-C1-C4-alkyl, Among them, C6-C 14 C6-C of the aryl-C1-C4-alkyl moiety 14-The aryl group is unsubstituted or substituted by one to five substituents independently selected from halogens, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, and C1-C4-haloalkoxy groups. R 2 With R 3 Identical and selected from C1-C4-alkyl groups, R 4 It is a C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenyl, or benzyl. n is 0, 1, or 2, and, Each substituent R 5 (If present) Independently selected from halogens, C1-C6-alkyl groups, and C1-C6-haloalkyl groups.

[0023] More preferably compounds of formula (Ia) or (Ib), especially (Ia), wherein the substituents are defined as follows: R 1 It is a C1-C6-alkyl group. R 2 With R 3 Identical and selected from C1-C4-alkyl groups, or R 2 With R 3 Together with the carbon atom it is attached to, it forms a C3-C6 cycloalkyl ring. R 4 It is a C1-C4-alkyl, C1-C4-haloalkyl, phenyl, or benzyl. n is 0, 1, or 2, and Each substituent R 5 (If present) Independently selected from halogens and C1-C6-alkyl groups.

[0024] Even more preferred are compounds of formula (Ia) or (Ib), especially (Ib), wherein the substituents are defined as follows: R 1 It is a C1-C4 alkyl group, preferably methyl, ethyl, or n-propyl. R 2 With R 3 Each of them is a methyl group. R 4 It is a C1-C4-alkyl group. n is 0, 1, or 2. Each substituent R 5 (If present) Independently selected from halogens and C1-C6-alkyl groups, preferably fluorine.

[0025] Even more preferred are compounds of formula (Ia) or (Ib), especially (Ia), wherein the substituents are defined as follows: R 1 It is methyl or n-propyl. R 2 With R 3 Each is a methyl group. R 4 It is methyl. n is 0 or 1, R 5 (If present) is fluorine.

[0026] Compounds of the most preferred formula (Ia) or (Ib), especially (Ia), wherein the substituents are defined as follows: R 1 It is methyl. R 2 With R 3 Each is a methyl group. R 4 It is methyl. n is 0.

[0027] The method of the present invention includes enantioselective hydrogenation of a compound of formula (II). The substituent R in the compound of formula (II) 1 R 2 R 3 R 4 R 5 and the integer n, each as defined in compounds of formula (Ia) or (Ib). For the substituent R of the compounds of formula (Ia) or (Ib) described above. 1 R 2 R 3 R 4 R 5 The meanings of preferred, more preferred, even more preferred, and most preferred integers n are as follows: refer to the compounds applicable to formula (II).

[0028] The enantioselective hydrogenation of compound (II) was carried out in the presence of a chiral iridium catalyst containing a chiral ligand of formula (IIIa) or (IIIb).

[0029] Preferably, the substituents in formulas (IIIa) and (IIIb) are defined as follows: R 6 Preferably, it is phenyl, which is either unsubstituted or substituted with one to five substituents independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl and tert-butyl.

[0030] R 6More preferably, it is selected from phenyl, 2-methyl-phenyl (o-tolyl), 3-methyl-phenyl (m-tolyl), 4-methyl-phenyl (p-tolyl), 2,6-dimethyl-phenyl, 3,5-dimethyl-phenyl and 2,4,6-trimethyl-phenyl (trimethyl-tolyl).

[0031] R 6 The most preferred selection is phenyl and 2,4,6-trimethyl-phenyl (trimethyl-phenyl).

[0032] R 7 Preferably selected from phenyl and naphthyl groups, The phenyl group is substituted with 1 to 5 substituents independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl, and the naphthyl group is either unsubstituted or substituted with 1 to 5 substituents independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl.

[0033] R 7 More preferably, it is selected from phenyl and naphthyl groups. The phenyl group is substituted by 1 to 5 substituents independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl, and the naphthyl group is unsubstituted.

[0034] R 7 Even more preferably, it is selected from 2-methyl-phenyl (o-tolyl), 3-methyl-phenyl (m-tolyl), 4-methyl-phenyl (p-tolyl), 2,6-dimethyl-phenyl, 3,5-dimethyl-phenyl, 2,4,6-trimethyl-phenyl (trimethyl-tolyl), 1-naphthyl and 2-naphthyl.

[0035] R 7 Even more preferably, it is selected from 2,6-dimethyl-phenyl, 3,5-dimethyl-phenyl and 2,4,6-trimethyl-phenyl (trimethyl-phenyl).

[0036] R 7 The preferred option is 2,6-dimethyl-phenyl.

[0037] R 8 Preferably, it is phenyl, which is substituted by 1 to 5 substituents independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl and tert-butyl.

[0038] R 8 More preferably, it is phenyl, which is substituted by one, two or three substituents independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl and tert-butyl.

[0039] R 8 Even more preferably, it is phenyl, which is substituted by one, two or three substituents independently selected from methyl and ethyl.

[0040] R 8 Even more preferred are o-tolyl, m-tolyl, p-tolyl, and mesityl.

[0041] R 8 The preferred formulation is o-tolyl or mestrilyl.

[0042] R 9 Preferably selected from C1-C6-alkyl, C3-C8-cycloalkyl and C6-C 14 -Aryl Wherein, the C1-C6-alkyl and C3-C8-cycloalkyl groups are unsubstituted or substituted with 1 to 3 substituents independently selected from halogens, C1-C4-alkoxy groups, C1-C4-haloalkyl groups, C1-C4-haloalkoxy groups, and phenyl groups, wherein the phenyl group is unsubstituted or substituted with 1 to 5 substituents independently selected from halogens, C1-C4-alkyl groups, C1-C4-alkoxy groups, C1-C4-haloalkyl groups, and C1-C4-haloalkoxy groups, and Among them, C6-C 14 -The aryl group is either unsubstituted or substituted with 1 to 5 substituents independently selected from halogens, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, and C1-C4-haloalkoxy.

[0043] R 9 More preferably, the radicals are selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. The phenyl group is either unsubstituted or substituted with one to five substituents independently selected from halogens, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, and C1-C4-haloalkoxy.

[0044] R 9 Even more preferred are those selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. The phenyl group is either unsubstituted or substituted with one to five substituents independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl.

[0045] R 9 Even more preferably, it is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl.

[0046] R 9 Even more preferred are those selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, and phenyl.

[0047] R9 The preferred methyl group is methyl.

[0048] Preferably, the enantioselective hydrogenation of the compound of formula (II) is carried out in the presence of a chiral iridium catalyst containing a chiral ligand of formula (IIIa) or (IIIb), wherein R 6 Selected from phenyl, 2-methyl-phenyl (o-tolyl), 3-methyl-phenyl (m-tolyl), 4-methyl-phenyl (p-tolyl), 2,6-dimethyl-phenyl, 3,5-dimethyl-phenyl, and 2,4,6-trimethyl-phenyl (trimethyl-tolyl). R 7 Selected from 2,6-dimethyl-phenyl, 3,5-dimethyl-phenyl, 2,4,6-trimethyl-phenyl (trimethyl-phenyl), 1-naphthyl, and 2-naphthyl. R 8 It is a phenyl group, which is substituted by one, two, or three substituents independently selected from methyl and ethyl groups, and R 9 It is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, and phenyl.

[0049] More preferably, the enantioselective hydrogenation of the compound of formula (II) is carried out in the presence of a chiral iridium catalyst containing a chiral ligand of formula (IIIa) or (IIIb), wherein R 6 It is phenyl or mesitylene. R 7 It is 2,6-dimethyl-phenyl. R 8 It is o-tolyl or mesitylene, and R 9 It is a methyl group.

[0050] Even more preferably, the compound of formula (II) undergoes enantioselective hydrogenation in the presence of a chiral iridium catalyst of formula (IV). in L For chiral ligands of formula (IIIa) or (IIIb) as defined above, L (1) It is 1,5-cyclooctadiene or norbornene. Y is a noncoordinate anion selected from [B(R 10 )4] - PF6 - SbF6 - CF3SO3 - [Al{OC(CF3)3}4] -(VI) and -TRISPHAT(VII), Where R 10 The phenyl group is selected from fluorine and phenyl, wherein the phenyl group is unsubstituted or substituted by 1 to 5 substituents independently selected from C1-C4-alkyl, C1-C4-haloalkyl and halogen.

[0051] Regarding L The chiral chelating ligands of formula (IIIa) or (IIIb) are preferred, more preferred, even more preferred and most preferred as defined above.

[0052] L (1) Preferably, it is 1,5-cyclooctadiene.

[0053] Y is preferably a noncoordinate anion selected from [B(R 10 )4] - PF6 - and [Al{OC(CF3)3}4] - (VI), Where R 10 It is a phenyl group, which is either unsubstituted or substituted with 1 to 5 substituents independently selected from C1-C4-alkyl, C1-C4-haloalkyl and halogen.

[0054] Y is more preferably selected from [B(R)] 10 )4] - and [Al{OC(CF3)3}4] - (VI) is a noncoordinate anion. Where R 10 It is a phenyl group, which is either unsubstituted or substituted with 1 to 5 substituents selected from fluorine and trifluoromethyl.

[0055] Y is optimally selected from [B(R)]. 10 )4] - The noncoordinated anion, of which R 10 It is 3,5-bis(trifluoromethyl)phenyl or 2,3,4,5,6-pentafluorophenyl.

[0056] Even more preferably, the enantioselective hydrogenation of the compound of formula (II) is carried out in the presence of a chiral iridium catalyst of formula (IV). in L For chiral ligands of formula (IIIa) or (IIIb), in R 6 It is phenyl or mesitylene. R 7 It is 2,6-dimethyl-phenyl. R 8 It is o-tolyl or mesitylene, and R 9 It is methyl. L (1) It is 1,5-cyclooctadiene, and Y is selected from [B(R)] 10 )4] - The sum of formula (VI) is [Al{OC(CF3)3}4] - noncoordinate anions. Where R 10 It is 3,5-bis(trifluoromethyl)phenyl or 2,3,4,5,6-pentafluorophenyl.

[0057] Even more preferably, the enantioselective hydrogenation of the compound of formula (II) is carried out in the presence of a chiral iridium catalyst of formula (IV). in L For chiral ligands of formula (IIIa) or (IIIb), in R 6 It is a phenyl group. R 7 It is 2,6-dimethyl-phenyl. R 8 It is mesitylene, and R 9 It is methyl. or R 6 It is mesitylene. R 7 It is 2,6-dimethyl-phenyl. R 8 It is o-tolyl, and R 9 It is methyl. L (1) It is 1,5-cyclooctadiene, and Y is a noncoordinate anion [B(R] 10 )4] - , where R 10 It is 3,5-bis(trifluoromethyl)phenyl or 2,3,4,5,6-pentafluorophenyl, preferably 3,5-bis(trifluoromethyl)phenyl.

[0058] Even more preferably, the enantioselective hydrogenation of the compound of formula (II) is carried out in the presence of a chiral iridium catalyst of formula (Va) or (Vb). in R 6 It is phenyl or mesitylene. R 7 It is 2,6-dimethyl-phenyl. R 8 It is o-tolyl or mesitylene. R 9 It is methyl, and Y is a noncoordinate anion [B(R] 10 )4] - , where R 10 It is 3,5-bis(trifluoromethyl)phenyl.

[0059] Most preferably, the enantioselective hydrogenation of the compound of formula (II) is carried out in the presence of a chiral iridium catalyst of formula (Va-1), (Vb-1), (Va-2), or (Vb-2). in R 6 It is a phenyl group. R 7 It is 2,6-dimethyl-phenyl. R 8 It is mesitylene. R 9 It is methyl, and Y is a noncoordinate anion [B(R] 10 )4] - , where R 10 It is 3,5-bis(trifluoromethyl)phenyl. in R 6 It is mesitylene. R 7 It is 2,6-dimethyl-phenyl. R 8 It is o-tolyl. R 9 It is methyl, and Y is a noncoordinate anion [B(R] 10 )4] - , where R 10 It is 3,5-bis(trifluoromethyl)phenyl.

[0060] Depending on whether the desired product is compound (Ia) or (Ib), select a ligand of formula (IIIa) or (IIIb).

[0061] As described above, the chiral iridium (P,S) ligand catalysts used in the methods of this invention are known from J. Margalef et al., Chem. Eur. J. 2014, 20, 12201-12214, or similar analogues. They can be prepared by the synthetic routes disclosed in the aforementioned references or similar references.

[0062] The amount of the chiral iridium (P,S)-ligand catalyst used is preferably 0.001 mol% to 5 mol%, more preferably 0.001 mol% to 4 mol%, most preferably 0.002 mol% to 3 mol%, particularly 0.005 mol% to 1.0 mol%, based on the amount of the compound of formula (II).

[0063] Preferably, hydrogenation is carried out using hydrogen gas at a pressure of 1 to 300 bar, more preferably 3 to 200 bar, and most preferably 20 to 150 bar.

[0064] Hydrogenation is preferably carried out at a temperature of 20°C to 130°C, more preferably 30°C to 100°C.

[0065] The method of the present invention is preferably carried out in the presence of a solvent.

[0066] Suitable solvents include haloalcohols such as 2,2,2-trifluoroethanol, hexafluoroisopropanol (1,1,1,3,3,3-hexafluoro-2-propanol) and tetrafluoropropanol (2,2,3,3-tetrafluoro-1-propanol), haloalkanes such as chlorobenzene, dichlorobenzene, dichloromethane, chloroform, tetrachloromethane, dichloroethane and trichloroethane, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane and anisole, and esters such as ethyl acetate, isopropyl acetate, and mixtures thereof.

[0067] Preferred solvents are selected from 2,2,2-trifluoroethanol, hexafluoroisopropanol, 1,2-dichloroethane, tetrafluoropropanol, 1,4-dioxane, isopropyl acetate, toluene, and mixtures thereof.

[0068] More preferred solvents are selected from 2,2,2-trifluoroethanol, hexafluoroisopropanol, 1,2-dichloroethane, tetrafluoropropanol, and mixtures thereof.

[0069] 2,2,2-trifluoroethanol and hexafluoroisopropanol are particularly preferred.

[0070] The optimal choice is hexafluoroisopropanol, namely 1,1,1,3,3,3-hexafluoro-2-propanol.

[0071] The amount of solvent (if present) is preferably 0.5 to 20 mass equivalents, more preferably 1 to 10 mass equivalents, most preferably 2 to 7 mass equivalents, and especially 4 to 6 mass equivalents, based on the amount of the compound of formula (II).

[0072] The method of the present invention is preferably carried out in the presence of additives selected from Brønsted acid and Lewis acid.

[0073] The additives are preferably selected from hexafluorophosphate, acetic acid, trifluoromethanesulfonic acid, water, pentafluorophenol, 3,5-bis(trifluoromethyl)phenol, tetrafluoroboric acid, tetrafluoroboric acid diethyl ether complex, perfluorosulfonic acid polymer (nafion), amberlyst, 1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)prop-2-ol, triphenylborane, tris[3,5-bis(trifluoromethyl)phenyl]borane, tris(2,3,4,5,6-pentafluorophenyl)borane, borane tetrahydrofuran complex, boric acid, aluminum trifluoromethanesulfonate (III), zinc trifluoromethanesulfonate (II), scandium trifluoromethanesulfonate (III), aluminum fluoride (III), isopropoxytitanium (IV), trimethylaluminum, boron trifluoride, boron trifluoride complex, and mixtures thereof.

[0074] Suitable boron trifluoride complexes are those of boron trifluoride with organic solvents (e.g., dialkyl ethers or alcohols) and those of boron trifluoride with organic acids (e.g., carboxylic acids). Preferred boron trifluoride complexes are selected from boron trifluoride diethyl ether complexes, boron trifluoride acetic acid complexes, and boron trifluoride n-propanol complexes.

[0075] More preferably, the additive is selected from hexafluorophosphate, pentafluorophenol, 3,5-bis(trifluoromethyl)phenol, tetrafluoroborate diethyl ether complex, triphenylborane, tris[3,5-bis(trifluoromethyl)phenyl]borane, tris(2,3,4,5,6-pentafluorophenyl)borane, aluminum trifluoromethanesulfonate (III), scandium trifluoromethanesulfonate (III), aluminum fluoride (III), isopropoxytitanium (IV), trimethylaluminum, boron trifluoride, boron trifluoride complex, and mixtures thereof, wherein the boron trifluoride complex is preferably selected from boron trifluoride diethyl ether complex, boron trifluoride acetic acid complex, and boron trifluoride n-propanol complex.

[0076] Even more preferably, the additive is selected from hexafluorophosphate, pentafluorophenol, 3,5-bis(trifluoromethyl)phenol, triphenylborane, tris[3,5-bis(trifluoromethyl)phenyl]borane, tris(2,3,4,5,6-pentafluorophenyl)borane, aluminum trifluoromethanesulfonate (III), scandium trifluoromethanesulfonate (III), aluminum fluoride (III), isopropoxytitanium (IV), trimethylaluminum, boron trifluoride, boron trifluoride complexes and mixtures thereof, wherein the boron trifluoride complex is preferably selected from boron trifluoride diethyl ether complexes, boron trifluoride acetic acid complexes and boron trifluoride n-propanol complexes.

[0077] Most preferably, the additive is selected from aluminum trifluoromethanesulfonate (III), scandium trifluoromethanesulfonate (III), tris(2,3,4,5,6-pentafluorophenyl)borane, hexafluorophosphate, boron trifluoride, and boron trifluoride complexes, wherein the boron trifluoride complexes are preferably selected from boron trifluoride diethyl ether complexes, boron trifluoride acetic acid complexes, and boron trifluoride n-propanol complexes.

[0078] If present, the amount of additives selected from Brønsted acids and Lewis acids is preferably 0.1 mol% to 10 mol%, more preferably 0.2 mol% to 5 mol%, most preferably 0.3 mol% to 2 mol%, especially 0.4 mol% to 1 mol%, based on the amount of the compound of formula (II).

[0079] Abbreviations and abbreviations: Example Preparation of chiral iridium (P,S)-ligand catalysts: Chiral ligands of formulas (IIIa) and (IIIb) and the corresponding chiral iridium (P,S)-ligand catalysts, such as chiral iridium (P,S)-ligand catalysts of formulas (Va) and (Vb), can be prepared according to the method disclosed by J. Margalef et al. in Chem. Eur. J. 2014, 20, 12201-12214, or by a similar method.

[0080] General steps for synthesizing chiral iridium (P,S)-ligand catalysts: The corresponding ligand (IIIa) or (IIIb) (0.074 mmol) was dissolved in CH2Cl2 (5 mL), and [Ir( [-Cl)(cod)]2 (25.0 mg, 0.037 mmol). The reaction mixture was heated and refluxed at 50°C for 1 hour. After standing at room temperature for 5 minutes, NaBArF (77.2 mg, 0.080 mmol) and water (5 mL) were added, and the reaction mixture was vigorously stirred at room temperature for 30 minutes. The phases were separated, and the aqueous phase was extracted twice with CH2Cl2. The combined organic phases were dried over magnesium sulfate, filtered through a diatomaceous earth column, and the solvent was evaporated to obtain an orange solid product.

[0081] Example 1, Synthetic (Va-1) chiral iridium (P,S)-ligand catalyst: The ligand of formula (IIIa-1) (where Mes is mesitylene) is prepared as follows: 0.55 mmol of bis(2,4,6-trimethylphenyl)phosphine chloride was dissolved in 2.5 mL of toluene, and pyridine (0.15 mL, 2.9 mmol) was added. 0.5 mmol of free alcohol (1R,2S)-1-((2,6-dimethylphenyl)thio)-3-methoxy-1-phenylprop-2-ol) was azeotropically dried over toluene and then dissolved in 2.5 mL of dried toluene containing pyridine (0.15 mL, 2.9 mmol). The alcohol solution was slowly transferred to a bis(2,4,6-trimethylphenyl)phosphine chloride / pyridine solution. The reaction mixture was stirred at 80°C for 90 min, and the pyridine salt was removed by filtration. Evaporation of the solvent yielded a white foam, which was purified by flash chromatography on alumina (toluene / NEt3 = 100:1) to give the corresponding ligand (IIIa-1) as a white solid.

[0082] Following the general steps outlined above, chiral iridium (P,S)-ligand catalysts of formula (Va-1) are prepared from ligands of formula (IIIa-1). in R 6 It is a phenyl group. R 7 It is 2,6-dimethyl-phenyl. R 8 It is mesitylene. R 9 It is methyl, and Y is a noncoordinate anion [B(R] 10 )4] - , where R 10 It is 3,5-bis(trifluoromethyl)phenyl.

[0083] Yield: 114 mg (89%). 31 P NMR (162 MHz, C6D6, 25℃, H3PO4): δ= 98.3 ppm(s). 1 H NMR (400 MHz, C6D6, 25℃, TMS): δ= 7.1-8.0 (m, 24H; CH= aromatic), 4.82(b, 1H; CH=, cod), 4.78 (s, 1H; CH-S), 4.62 (b, 1H; CH=, cod), 4.40 (m, 1H;CH-O), 3.64 (m, 1H; CH=, cod), 3.37 (m, 1H; CH2), 3.16 (m, 1H; CH2), 3.11 (s,3H; CH3-O), 2.94 (b, 1H; CH=, cod), 2.41 (m, 2H; CH2 cod), 2.82 (s, 3H; CH3),2.1-2.4 (m, 9H; CH2 cod and CH3), 2.08 (s, 3H; CH3), 2.00 (s, 3H; CH3), 1.79 (s,6H; CH3), 1.71 (s, 3H; CH3), 1.67 ppm (s, 3H; CH3). 13C NMR (126 MHz, C6D6, 25℃, TMS): δ = 161.9 (q, 1J(C,B) = 49.9 Hz; CB, BArF), 117.6–143.0 (aromatic carbon), 101.3 (d, J(C,P) = 12.4 Hz; CH=, cod), 98.4 (d, J(C,P) = 9.2 Hz; CH=, cod), 79.8 (d, 2J(C,P) = 3.6 Hz; CH-O), 75.9 (s; CH=, cod), 70.9 (s; CH=, cod), 64.9 (d, 3J(C,P) = 4.0 Hz; CH2), 59.3 (s; CH3-O), 58.4 (s; CH-S), 33.0 (s; CH2, cod), 32.1 (s; CH2, cod), 30.1 (s; CH2, cod), 29.1 (b; CH2, cod), 23.2(s; CH3), 22.5 (s; CH3), 22.3 (s; CH3), 22.1 (s; CH3), 22.0 (s; CH3), 21.9(s; CH3), 20.6 ppm (s; CH3). MS HR-ESI [measured 871.3272, C 44 H 55 IrO2PS (M-BArF) + Theory 871.3284].

[0084] Example 2, Synthetic (Va-2) chiral iridium (P,S)-ligand catalyst: The ligand of formula (IIIa-2) (where Tol is o-tolyl) has been prepared in a manner similar to that used for the preparation of the ligand of formula (IIIa-1) described above. Following the general steps outlined above, a chiral iridium (P,S)-ligand catalyst of formula (Va-2) is prepared from the ligand of (IIIa-2). in R 6 It is mesitylene. R 7 It is 2,6-dimethyl-phenyl. R 8 It is o-tolyl. R 9 It is methyl, and Y is a noncoordinate anion [B(R] 10 )4] - , where R 10 It is 3,5-bis(trifluoromethyl)phenyl.

[0085] Yield: 115 mg (92%). 31 P NMR (162 MHz, CDCl3, 25℃, H3PO4): δ= 105.2 ppm(s). 1 H NMR (400 MHz, CDCl3, 25℃, TMS): δ= 6.62-7.93 (m, 25 H; CH=aromatic), 4.79(m, 1 H; CH-O), 4.61 (m, 1 H; CH= cod), 4.17 (b, 2 H; CH-S, CH=, cod), 3.91(b, 1 H; CH=, cod), 3.12 (m, 2 H; CH2, CH= cod), 2.99 (s, 3 H; CH3-O), 2.96(b, 1 H; CH2), 2.93 (s, 3 H; CH3), 2.67 (s, 3 H; CH3), 2.54 (b, 1 H; CH2, cod), 2.52 (s, 3 H; CH3), 2.13 (s, 6 H; CH3), 1.9-2.4 (b, 7 H; CH2, cod), 1.72 (s, 3 H; CH3), 1.12 ppm (s, 3 H; CH3). 13C NMR (126 MHz, CDCl3, 25℃, TMS): δ=161.8 (q, 1J(C,B) = 49.8 Hz; CB, BArF), 117.6-144.5 (aromatic carbon), 101.2 (d, J(C,P) = 12.5 Hz; CH=, cod), 99.1 (d, J(C,P) = 12.1 Hz; CH=, cod), 73.4 (s; CH=,cod), 79.5 (s; CH-O), 72.4 (d, 3J(C,P) = 6.9 Hz; CH2), 70.2 (s; CH=, cod), 58.9 (s; CH3-O), 50.1 (s; CH-S), 34.0 (b; CH2, cod), 30.3 (d, J(C,P) = 3.2 Hz; CH2, cod), 30.1 (s; CH2, cod), 27.0 (s; CH2, cod), 23.6 (s; CH3), 22.9 (s; CH3), 22.4 (s; CH2), 21.6 (s; CH3), 21.3 (s; CH2), 20.7 (s; CH3), 19.3 ppm (s; CH3). MS HR-ESI [Measured 855.3103, C 43 H 53 IrO2PS (M-BArF) + Theory 855.3104].

[0086] Comparative Examples 3-5, comparative chiral iridium (P,S)-ligand catalysts of synthetic formulas (Va-3), (Va-4), and (Va-5): Comparative example ligands of formulas (IIIa-3), (IIIa-4), and (IIIa-5) were prepared using methods similar to those described in Examples 1 and 2, wherein Ph is phenyl and Tol is o-tolyl. Following the general steps outlined above, comparative chiral iridium (P,S)-ligand catalysts of formulas (Va-3), (Va-4), and (Va-5) were prepared from ligands of the corresponding formulas (IIIa-3) to (IIIa-5). Where R 6 R 7 R 8 and R 9 The meanings are given in Table 1, and Y is a noncoordinate anion [B(R]10 )4] - , where R 10 It is 3,5-bis(trifluoromethyl)phenyl.

[0087] Table 1: Hydrogenation of 4-substituted 1,2-dihydroquinoline: Examples 6 and 7, and Comparative Examples 8 to 10: TMQA (300 mg, 1.4 mmol) and 2.8 µmol Ir catalyst (Va-1), (Va-2), or one of the comparative catalysts Va-3 to Va-5 shown in Table 2 were added to a 20 mL glass vial equipped with a cross-shaped stir bar. The vial was sealed with a diaphragm and purged under 1.2 bar argon for 10 min. Then HFIP (2.8 mL) was added, and the mixture was stirred for 1 min. The vial was then punctured with a needle and quickly transferred to an autoclave, which was sealed under a positive argon atmosphere (1.2 bar). Hydrogen gas was then introduced into the autoclave at 20 bar and released (repeated 3 times), and finally pressurized to 40 bar. The autoclave was heated to 45 °C and stirred at 690 rpm. After 2.5 hours, the autoclave was cooled to room temperature, and the pressure was carefully released. The solution was analyzed by gas chromatography. Results and other reaction details are given in Table 2.

[0088] Table 2: Comparative Example 8 shows that the sulfur atom has a tert-butyl substituent (R). 7 Phosphorus atoms have phenyl substituents (R) 8 The catalyst (Va-3) was insufficient in the target hydrogenation reaction, both in terms of conversion (4%) and enantiomeric excess (<2%). If only the substituents on the phosphorus atom (R) were added... 8 Replacing the substituent (R) with a larger-volume o-tolyl residue (as in catalyst (Va-4)) did not result in any improvement (see Comparative Example 9). If only the substituent on the sulfur atom (R) is replaced... 7 Replacing R with a larger-volume 2,6-dimethyl-phenyl residue (as in catalyst (Va-5)) resulted in some improvement, but still insufficient (see Comparative Example 10; conversion = 12%, enantiomeric excess = 40%). Surprisingly, if R 7 and R 8 These are all residues with significant steric hindrance, such as in the catalyst (Va-1) (R 7 =2,6-Dimethyl-phenyl, R 8In the case of 0.5-trimethylbenzene, a significant increase in both conversion and enantiomeric excess was observed (see Example 6; conversion = 95%, enantiomeric excess = 64%).

[0089] Example 7, using a catalyst (Va-2), also demonstrates that if the catalyst is located at the sulfur atom (R... 7 (2,6-dimethylphenyl) and phosphorus atom (R) 8 By having large-volume substituents on the o-tolyl group, improved conversion and enantiomeric excess can be obtained.

[0090] Examples 11 and 12: Hydrogenation in the presence of additive BF3·OEt2 TMQA (300 mg, 1.4 mmol) and 2.8 µmol Ir catalyst (Va-1) or (Va-2) (as shown in Table 3) were added to a 20 mL glass vial equipped with a cross-shaped stir bar. The vial was sealed with a diaphragm and purged under 1.2 bar argon for 10 min. Then HFIP (2.8 mL) was added and the mixture was stirred for 1 min. Then BF3·OEt2 (1 µL) was added, the glass vial was punctured with a needle, and the mixture was quickly transferred to an autoclave, which was then sealed under a positive argon atmosphere (1.2 bar). Hydrogen was then introduced into the reactor at 20 bar and released (repeated 3 times), and finally pressurized to 40 bar of hydrogen. The reactor was heated to 45°C and stirred at 690 rpm. After 2.5 hours, the reactor was cooled to room temperature and the pressure was carefully released. The solution was analyzed by gas chromatography. Results and other reaction details are shown in Table 3.

[0091] Table 3: Comparing the results of Examples 11 and 12 with those of Examples 6 and 7 shows that the presence of additive BF3·OEt2 further improves the conversion and / or enantiomeric excess, thereby promoting the desired reaction.

Claims

1. A process for the preparation of a compound of formula (la) or (lb) R 1 Selected from C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl, C6-C 14 -Aryl and C6-C 14 -aryl-C1-C4-alkyl, wherein C1-C6-alkyl, C3-C6-cycloalkyl and C1-C6-alkoxy-C1-C6-alkyl moieties the C1-C6-alkoxy groups are unsubstituted or substituted with one to three substituents each independently selected from the group consisting of halogen, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy and phenyl, wherein the phenyl groups are unsubstituted or substituted with one to five substituents each independently selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl and C1-C4-haloalkoxy, and, Among them, C6-C 14 -Aryl and C6-C 14 C6-C of the aryl-C1-C4-alkyl moiety 14 -The aryl group is, in its respective case, unsubstituted, or substituted by one to five substituents independently selected from halogens, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, and C1-C4-haloalkoxy groups. R 2 are identical with R 3 and are selected from the group consisting of hydrogen, Ci-C6-alkyl, Ci-C6-haloalkyl and Ci-C6-alkoxy-Ci-C6-alkyl, or R 2 With R 3 Together with the carbon atoms they are attached to, they form C3-C6-cycloalkyl rings. R 4 Selected from hydrogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylamino, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-C1-C4-alkyl, C2-C6-alkenyloxy, 9-fluorenylmethyleneoxy, C6-C 14 -Aryl, C6-C 14 -Aryloxy group, C6-C 14 -aryl-C1-C4-alkyloxy and C6-C 14 -aryl-C1-C4-alkyl, C6-Cio-aryl, which - as a mono- or disubstituent - is unsubstituted or carries 1, 2 or 3 substituents, in particular 1 or 2 substituents, each independently selected from the group consisting of halogen, CN, C1-C4-haloalkyl, C3-C6-cycloalkyl, C3-C6-halogencycloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy, 14 - aryl is unsubstituted or carries 1 to 5 substituents, independently of one another, selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy, n is 0, 1, 2, 3 or 4, Each substituent R 5 If present, independently selected from halogens, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, hydroxyl, amino, and -C(=O)-C1-C6-alkyl. the process comprising enantioselective hydrogenation of a compound of formula (II) wherein the substituents R 1 , R 2 , R 3 , R 4 , R 5 and the integer n are each as defined in the compound of formula (Ia) or (Ib), characterized in that the chiral iridium catalyst contains a chiral ligand of formula (IIIa) or (IIIb) wherein R 6 is C6-C 14 - aryl, which is unsubstituted or substituted by one to five substituents selected independently of one another from the group consisting of C1-C4-alkyl, R 7 selected from phenyl, naphthyl and anthryl, wherein the phenyl groups are substituted with one to five substituents each independently selected from the group consisting of C1-C4-alkyl, and the naphthyl and anthryl groups are each unsubstituted or substituted with one to five substituents each independently selected from the group consisting of C1-C4-alkyl, Each R 8 For C6-C 14 -aryl group, which is substituted by 1 to 5 substituents independently selected from C1-C4-alkyl groups, and R 9 selected from the group consisting of Ci-C6-alkyl, C3-C8-cycloalkyl and C6-Ci2-aryl, 14 - aryl, wherein the C1-C6-alkyl and C3-C8-cycloalkyl groups are unsubstituted or substituted with one to three substituents each independently selected from the group consisting of halogen, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy and phenyl, wherein the phenyl groups are unsubstituted or substituted with one to five substituents each independently selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl and C1-C4-haloalkoxy, and, wherein the C6-Ci4-aryl is unsubstituted or substituted by 1 to 5 substituents selected, independently from each other, from the group consisting of halogen, Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy and Ci-C4-haloalkoxy, 14 - aryl is unsubstituted or substituted by 1 to 5 substituents selected, independently from each other, from the group consisting of halogen, Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy and Ci-C4-haloalkoxy, or R 9 is a carrier material selected from the group consisting of polyether, polystyrene, silica and alumina.

2. The process according to claim 1, wherein R 1 C6-C10-cycloalkyl or C7-C12-aryl, each of which is unsubstituted or substituted by 14 - C6-C10-aryl-C1-C4-alkyl, Among them, C6-C 14 C6-C of the aryl-C1-C4-alkyl moiety 14 -The aryl group is unsubstituted or substituted by one to five substituents independently selected from halogens, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, and C1-C4-haloalkoxy groups. R 2 is the same as R 3 and is selected from the group consisting of Ci-C4-alkyl, R 4 is Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, phenyl or benzyl, n is 0, 1 or 2, and, Each substituent R 5 If present, it is independently selected from halogens, C1-C6-alkyl groups, and C1-C6-haloalkyl groups.

3. The process according to claim 1, wherein R 1 is Ci-C4-alkyl, R 2 with R 3 is methyl, R 4 is Ci-C4-alkyl, n is 0 or 1, R 5 if present, is fluorine.

4. The process according to any one of claims 1 to 3, wherein R 6 is phenyl, which is unsubstituted or substituted by one to five substituents, selected independently from each other, from methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl.

5. The method of any one of claims 1 to 3, wherein R 6 is phenyl or mesityl.

6. The process according to any one of claims 1 to 3, wherein R 7 selected from phenyl and naphthyl, wherein the phenyl groups are substituted with one to five substituents each independently selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl, and the naphthyl groups are unsubstituted or substituted with one to five substituents each independently selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl.

7. The method of any one of claims 1 to 3, wherein R 7 is 2,6-dimethyl-phenyl.

8. The process according to any one of claims 1 to 3, wherein R 8 is phenyl, which is substituted with 1 to 5 substituents, independently selected from each other, from methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl.

9. The method of any one of claims 1 to 3, wherein R 8 is o-tolyl or mesityl.

10. The method of any one of claims 1 to 3, wherein R 9 is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, and phenyl.

11. The method of any one of claims 1 to 3, wherein R 9 is methyl.

12. The process according to any one of claims 1 to 3, wherein the chiral iridium catalyst is a catalyst of formula (IV) wherein L is a chiral ligand of formula (IIIa) or (IIIb), as defined in any one of claims 1 and 4 to 11, L (1) is 1,5-cyclooctadiene or norbornadiene, Y is a non-coordinating anion selected from the group consisting of [B(R 10 )4] - , PF6 - , SbF6 - , CF3SO3 - , [Al{OC(CF3)3}4] - (VI) and - TRISPHAT (VII), wherein R 10 is selected from fluorine and phenyl, which phenyl is unsubstituted, or substituted by one to five substituents selected independently from one another from C1-C4-alkyl, C1-C4-haloalkyl and halogen.

13. The process according to claim 12, wherein L is a chiral ligand of formula (IIIa) or (IIIb), wherein R 6 is phenyl or mesityl, R 7 is 2,6-dimethyl-phenyl, R 8 is ortho-tolyl or mesityl, and R 9 is methyl, L (1) is 1,5-cyclooctadiene, and Y is a non-coordinating anion selected from the group consisting of [B(R 10 )4] - and [Al{OC(CF3)3}4] of formula (VI) - , wherein R 10 is 3,5-bis(trifluoromethyl)phenyl or 2,3,4,5,6-pentafluorophenyl.

14. The process according to any one of claims 1 to 3, wherein the chiral iridium catalyst is a catalyst of formula (Va) or (Vb) wherein R 6 is phenyl or mesityl, R 7 is 2,6-dimethyl-phenyl, R 8 is o-tolyl or mesityl, R 9 is methyl, and Y is a non-coordinating anion [B(R 10 )4] - wherein R 10 is 3,5-bis(trifluoromethyl)phenyl.

15. The process according to any one of claims 1 to 14, wherein the process is carried out in the presence of an additive selected from hexafluorophosphoric acid, pentafluorophenol, 3,5-bis(trifluoromethyl)phenol, triphenylborane, tris[3,5-bis(trifluoromethyl)phenyl]borane, tris(2,3,4,5,6-pentafluorophenyl)borane, aluminum(III) trifluoromethanesulfonate, scandium(III) trifluoromethanesulfonate, aluminum(III) fluoride, titanium(IV) isopropoxide, trimethylaluminum, boron trifluoride, boron trifluoride complexes, and mixtures thereof.

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